Eeg feedback controlled sound therapy for tinnitus

ABSTRACT

An automated method for treating tinnitus by habituation through use of neurological feedback, comprising the steps of connecting a subject through a set of attached headphones to an electronic sound player that is connected to a PC workstation presenting sound examples by software to the subject who can refine them by manipulating a series of controllers on the player, making an electronic recording of the sound in a digital music format, storing the recording in the computer, transferring a copy of the electronic sound file to the subject&#39;s electronic music player, generating an EEC signature of the subject&#39;s brain activity in response to the presented sound, sound using the customized sound to stimulate the auditory system while the brain activity is recorded, wherein the computer continuously monitors for the feedback signatures and drives the sound stimuli appropriately.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention generally concerns the diagnosis and treatment oftinnitus. The invention more specifically relates to the use of customdesigned sound and feedback to determine the precise treatment soundmatching the tinnitus, its neurophysiological effect, and monitoring thetreatment effect by feedback from the brain.

2. Description of Related Art

Commonly perceived as a “ringing in the ear,” tinnitus is a veryfrequent disorder of the auditory system, affecting about 17% of thegeneral population and up to 33% in the elderly. About a quarter ofthese people are sufficiently bothered by their tinnitus that they seekprofessional help [Jastreboff et al, 1996]. Tinnitus is a phantomperception and thus not associated with any auditory stimulus. Untilvery recently, there were no objective measurements that could berelated to tinnitus [Jastreboff et al, 1994], and diagnosis of tinnitushad to rely on various questionnaires, e.g. [Wilson et al, 1991]. Thefact that tinnitus is perceived as a sound, however, indicates that itis associated with aberrant neural activity in the auditory pathways.Furthermore, the fact that tinnitus is associated with perception leadsto the conclusion that central auditory structures such as the thalamusand auditory cortex must be involved. Neural correlates of tinnitus haveindeed been found in central auditory structures [Norena et al, 1 999;Mühlnickel et al, 1 998; Wallhäusser-Franke et al, 1996]. Previously,tinnitus had been viewed as being caused in the auditory periphery[Eggermont, 1990; Tonndorf, 1981; Salvi and Ahroon, 1983], and eventhough neuronal activity related to tinnitus has been found in thecentral auditory system rather than in the periphery, it remainspossible that the chain of events that leads to the development oftinnitus may be set off by events taking place in the periphery.

A Thalamic Model of Tinnitus

The presence of tinnitus-related neural activity in the central auditorysystem agrees well with a recently proposed neurophysiological model oftinnitus [Jeanmonod et al, 1996] (FIG. 1). According to the model,tinnitus arises in the thalamus. Several parts of the thalamus interactto establish a reverberating loop. Neuronal activity originating fromthis reverberating loop is transmitted to the auditory cortex, where itgives rise to the tinnitus perception. This reverberating loop isestablished by disinhibition of neurons in the thalamus, which occurswhen thalamic neurons receive inhibitory input causing ahyperpolarization. These thalamic neurons are capable of generatingaction potentials, once the hyperpolarization has reached a threshold.Thus, inhibitory input can cause these neurons to fire. The actionpotentials generated by this mechanism are called low threshold spikes(LTS) and usually occur in rhythmic bursts.

Two structures in the thalamus receive afferent auditory input: themedial geniculate body (MGB) and the multimodal medial thalamus (MT).Both these nuclei give excitatory input to the thalamic reticularnucleus (RT), and in turn receive inhibitory input from the RT. Whenafferent input into the MGB is normal, an equilibrium of excitation andinhibition is present in both MT and MGB (FIG. 1A). When the afferentauditory input into the thalamus fails, an imbalance of input iscreated. The MGB will receive no input whereas the MT receives aslightly decreased input (FIG. 1B). In this situation, the RT will stillreceive excitatory input from the MT, enough to generate the inhibitoryoutput to both MT and MGB (FIG. 1C). Since no excitation is present inthe MGB, the inhibitory input from the RT will hyperpolarize the neuronsin the MGB. Neurons in the MGB will respond to this hyperpolarizationwith deinactivation leading to LTS bursts that are propagated to theauditory cortex (FIG. 1D).

Damage to the basilar membrane can set off the thalomocorticalreverberating loop.

This model explains the appearance of tinnitus in conditions where theMGB is not receiving sensory input, e.g. in silent environments, or whenhearing thresholds are temporarily or permanently raised after noiseexposure. According to this model, once input into the MGB is restored,the tinnitus should vanish. Clearly, this is not the case in thosepeople who are so annoyed by their tinnitus that they seek professionalhelp. An additional mechanism must be in place to make tinnitus persist.

It has been noted that the presence of tinnitus cannot be determinedfrom an audiogram, i.e. tinnitus may be present even when the MGB isreceiving normal sensory input. The perception of tinnitus will only bestabilized when the person perceiving the phantom noise pays attentionto it and associates it with unpleasant emotions [Jastreboff et al,1996b; Langner and Wallhäusser-Franke, 1999](FIG. 2). In this scenario,the person experiencing tinnitus is annoyed by it. Consequently, he willdirect his attention to the phantom sound, thereby activating the limbicsystem. The limbic system is assumed to give rise to an increasedgeneration of tinnitus-related activity. The detection oftinnitus-related activity is facilitated by mechanisms of lateralinhibition in the central auditory system. These will act to confine thephantom sound to regions representing distinct frequencies and increasethe contrast between the tinnitus-related activity in these regions andthe spontaneous activity in adjacent regions. This will lead toincreased tinnitus perception. The increased perception can then lead toincreased annoyance, completing a positive feedback cycle that will maketinnitus persistent.

The Auditory N100 As an Index of Cortical Responsiveness

Event-related potential (ERP) studies have demonstrated that electricalactivity time-locked to stimulus or response events and averaged overrepeated trials reflects information processing in the cortex [Hillyardet al, 1978; Pritchard, 1981b; Duncan-Johnson and Donchin, 1977; Pinedaet al, 1997; Pineda et al, 1998]. Considerable evidence to dateindicates that long-latency potentials (approximately >100 mspoststimulus) appear primarily sensitive to cognitive variables thatreflect task requirements and the psychological state of the subject.These “endogenous” potentials most likely reflect non-obligatoryactivities invoked by the demands of the task.

One of the most widely studied endogenous components is the N100. Wolpawand Penry [Wolpaw and Penry, 1975] were the first to propose that theN100 consisted of midline and temporal subcomponents. Subsequent workhas shown that midline components can be modeled with tangentialgenerators on the superior temporal plane and pointing toward themidline of the scalp. At least two midline components have beendistinguished. An early frontocentral peak (N100a) shows reliabletonotopic changes in distribution and sensitivity to attention [Woods,1995]. A later midline component (N100b) shows the same distribution fortones of different frequency.

N100 components show increases in amplitude and decreases in latencywith increasing stimulus intensity [Hillyard et al, 1978; Scherg and vonCramon, 1990; Mäkelä and Hari, 1990]. In some individuals, the increasesin stimulus intensity often bring decreased amplitude and increasedlatency. This tendency for N100 to increase or decrease in magnitude inresponse to stimuli of increasing intensity has been called the“augmenting/reducing” (AR) response. These intensity-amplitude functionshave been hypothesized to result from variations in the centralmodulation of sensory processing and/or the actions of nonspecificarousal systems [Zuckermann et al, 1974; von Knorring and Perris, 1981].It has also been proposed that they.may reflect the “tuning” propertiesof a cortical gating mechanism that regulates sensory input [Buchsbaumand Silverman, 1968; Lukas and Siegel, 1977; Pritchard et al, 1985].Some have related this mechanism to “attention” shifts and “overload”protection at high stimulus intensities.

A number of studies have shown that midline auditory N100 shows strongintensity dependence, while those recorded from temporal electrodes showweak intensity dependence [Pineda et al, 1991]. These differencessuggest different N100 generators in the primary and secondary auditoryareas [Pineda et al, 1991] [Connally, 1993], which is consistent withthe multiple N100 generator hypothesis [Woods, 1995].

How Thalamo-Cortical Activity Affects the A/R-Response

The rhythmic LTS bursting activity of thalamic neurons mentioned aboveis also observed in slow wave sleep [Pape and McCormick, 1989; Steriadeand Llinas, 1988], where it is thought to be a gating mechanism blockingsensory input into the cortex [Pape and McCormick, 1989; Steriade andLlinas, 1988]. The argument has also been made that this mechanism isactive not only during sleep but also during waking and may result indifferent attentional states. The excitation of cortical tissue bytinnitus may compete with stimulus-induced activity. The neural activityinduced by the tinnitus may, therefore, be regarded as competition forcortical neuronal substrates. This may lead to the reorganization of theauditory cortex [Mühlnickel et al, 1998]. That is, the processing ofstimuli in the presence of tinnitus-related activity may lead toincreases in the firing rate of neurons, the use of more neuralsubstrate, or a combination of both. It is hypothesized that thesemechanisms for dealing with tinnitus-related activity in the auditorysystem lead to the increased intensity dependence of the auditory evokedpotential that Inventors and others have observed [Norena et al, 1999].

The hypothesis that tinnitus-related neural activity is caused byoscillatory LTS activity in the thalamus is further supported by acombination of other findings. First, application of serotonin in thelateral geniculate body (LGB) or MGB of the cat suppresses thehyperpolarization necessary to generate LTS-bursts [Pape and McCormick,1989]. Second, the intensity dependence of the auditory evoked potentialis strongly influenced by brain serotonergic activity [Juckel et al,1999; Juckel et al, 1997; Hegerl et al, 1996]. Finally, theseobservations are linked by the fact that the thalamus contains a highdensity of binding sites for serotonergic drugs as well as serotoninuptake sites [Smith, 1999].

Elaboration on the Tinnitus Models

Taken together the various models and evidence suggest that whiletinnitus may be triggered by events in the periphery, the mechanismsthat make tinnitus a persistent and annoying condition are located inthe central auditory system. Furthermore, it appears that peoplesuffering from tinnitus unintentionally train themselves to havetinnitus by using negative reinforcement. It has been shown that thecortical representation of tones associated with unpleasant sensationsis enlarged [Gonzalez-Lima and Scheich, 1986] and/or changed to enhancethe contrast between this particular tone and other tones of similarfrequency [Ohl and Scheich, 1996]. The cortical representation of tonesno longer associated with unpleasant sensations will return to a statewhere contrasts are no longer enlarged. Moreover, responses to stimulioccurring while attention is directed at another task will decrease overtime [Anderson and Oatman, 1980]. This suggests that if the associationbetween tinnitus and unpleasant emotions can be broken, the aberrantneuronal activity in the central auditory system can be decreased byhabituation. Then tinnitus is treated like any other sound that does notcarry relevant information: it is ignored. The tinnitus retrainingtherapy (TRT) introduced by Jastreboff [Jastreboff et al, 1996a] makesuse of the mechanism described above. However, TRT as described byJastreboff uses white or broadband noise as a habituating stimulus. Therationale behind the use of white noise is to generate a decreasedsignal-to-noise ratio between the tinnitus-related neuronal activity andrandom background activity in the auditory system. This would beachieved by introducing a quasi-random, stimulus-driven activity intoall of the parallel tonotopic channels of the auditory system.

A precise computational model of tinnitus has been proposed by Langneret al [Langner and Wallhäusser-Franke, 1999] based on animal work. Thismodel assumes that the limbic system is necessary for stabilizing thetinnitus perception. It also explains how a decreased auditory inputresulting from a peripheral hearing deficit can give rise to a specifictinnitus pitch. When the tinnitus sound is used as a habituationstimulus, Langners' model predicts the tinnitus would disappear.

Currently, there are sound therapies for tinnitus that use genericsounds. These present therapies are only partially effective and requirea long time for treatment. It would, therefore, be desirable to obtain abrain signal feedback system, wherein one could rapidly suppress brainactivity related to tinnitus and provide relief for this disorder.

SUMMARY OF THE INVENTION

To address the beforementioned problem and the above solution theinventors disclose their invention as follows.

The invention contemplates an automated method for treating tinnitus byhabituation to customized sound through use of neurological feedback.The methodology comprises the following steps. The tinnitus-sufferingsubject is connected through headphones to an electronic sound playerthat in turn is connected to a PC workstation. A customized soundprofile is created for the subject's particular tinnitus by presenting aplurality of audible sound examples from a tinnitus sound library inspecial software. The subject is allowed to choose and refine thepresented sounds that most closely resemble his or her tinnitus sound.The refined sound is recorded in a digital music format to create acustom sound profile for that particular subject, and the custom soundprofile recording is stored in a computer.

An EEG signature of the subject's brain activity in response to thepresented sound is generated by downloading a copy of the electronicsound file to the subject's electronic music player, presenting customsound most closely matching the tinnitus to stimulate the auditorysystem, and recording the subject's neurological response to soundsadjacent to but not specifically corresponding to his tinnitussignature. The subject's brain activity during absence of sound stimuliis also recorded. The EEG profile is uploaded into the computer tocreate the EEG signature. When undergoing treatment, the EEG response isactively monitored by the computer, which generates sound in response.The computer periodically tests the signatures for tinnitus and silenceand determines if the tinnitus is decreasing and the silence signal isstrengthening, and when if these desirable changes are not present, thecomputer slightly alters the sound stimuli and again checks forfeedback. Thus, the computer continuously monitors for the feedbacksignatures and drives the sound stimuli appropriately to habituate thesubject to his tinnitus.

A method is also contemplated by this invention for customizedhabituation treatment of tinnitus without masking sound or usingsubthreshold sound. This method involves matching narrowband soundfrequency to a patient's perceived tinnitus and presenting the matchedsound frequency to the subject, wherein the presented matched soundactivates the same population of neurons affected by tinnitus, andwherein habituation occurs when the tinnitus and the habituatingstimulus sound are as much alike as possible. Periodically, frequencychanges are updated as required for maintaining maximum habituation.

An objective method for diagnosing tinnitus by detecting changes in thedynamic response characteristics of the auditory cortex induced bytinnitus is further contemplated. This method comprises characterizing asubject's tinnitus perception by matching the pitch of his or hertinnitus to the frequency of a pure sine tone generated by a functiongenerator, having a programmable logarithmic amplifier that iscontrolled in real time by a stimulus presentation and data collectionprogram software to set the intensity of each stimulus. An auditoryevoked potential to a variety of tone pitches, including the tinnituspitch is recorded, wherein the increased activation of the auditorycortex manifests itself as an increased slope of the AR. The slope ofthe AR response for tinnitus frequency tones is calculated, wherein anobserved increase in the slope of the AR in tinnitus indicatestinnitus-related activity present in the auditory cortex.

Another preferred method for treating tinnitus by habituation to itssound frequency comprises the steps of determining the “matchingfrequency” (pitch) of a subject's tinnitus, determining the hearingthreshold for the tinnitus frequency; determining the “matchingintensity” of the subject's tinnitus, and determining the hearingthreshold for the “off” frequencies. This is followed by stimulating theauditory system in two series of tonal stimulation; first at thetinnitus frequency, and second at the “off” frequency. EEG data iscollected and the subject is given an electronic music player having thehabituation stimulus downloaded into it. The subject is asked to listento the player for as long as it is comfortable each day.

The “matching frequency” is determined by presenting the subjects with acontinuous, audible tone varying in pitch, and asking them to indicatethe frequency most closely matching the frequency of their tinnitus. Todetermine the threshold, subjects are presented with a continuous tonethat gradually increases in volume, and are asked to indicate when theybegin to hear the tone. The intensity at which the subjects begin tohear the tone is considered the hearing threshold. “Matching intensity”is determined when subjects are presented with a continuous tone thatincreases or decreases in volume and are asked to indicate the momentwhen they perceive the tone as being of the same loudness as theirtinnitus.

An EEG marker of tinnitus suitable for diagnosing the presence oftinnitus is also contemplated by this invention. This marker comprises areplica of a subject's tinnitus sound experience and a measure of thesubject's EEG response to increasing intensity of the sound. The replicaof sound is constructed from a subject's subjective determination ofsound most closely related to the annoying sound experienced by him, andthe patients EEG response is measured to determine peak amplitude of theN100 component.

These and other aspects and attributes of the present invention willbecome increasingly clear upon reference to the following drawings andaccompanying specification.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the development of tinnitus (adapted from Jeanmonod et al1996). There is afferent auditory input to the medial geniculate body(MGB) and the multimodal medial thalamus (MT). Both these nuclei giveexcitatory input to the thalamic reticular nucleus (RT), and in turnreceive inhibitory input from the RT. Further explanation is in thetext.

FIG. 2 is an overview of the auditory system with regard to tinnitusgeneration and the Mechanisms stabilizing tinnitus. Adapted fromJeanmonod 1996 and Langner 1999. Explanation is in the text.

FIG. 3 displays the auditory-evoked potential at the electrode positionFz, recorded at 30 dB (LOW), 42 dB (MED) and 54 dB (HIGH) above thesubject's hearing threshold. Note that the amplitude of the N100component increases with increasing stimulus volume.

FIG. 4 shows the auditory-evoked potential at the electrode position Fz,recorded using various references. The stimulus was a 1 kHz tonepresented at 54 dB above the subject's hearing threshold. The stimuluswas presented 80 times in each condition.

FIG. 5 demonstrates that the intensity dependence of both amplitude(top) and latency (bottom) the N100 component of the auditory evokedpotential in tinnitus subjects is changed by one hour of habituationtraining. (N=4).

FIG. 6 reveals that neither the intensity dependence of amplitude (top)or latency (bottom) the N100 component of the auditory evoked potentialin normal control subjects is affected by a one hour exposure to narrowband noise. (N=2)

FIG. 7 further shows that the intensity dependence of the N100 componentof the auditory evoked potential varies with stimulus frequency. Notethat the A/R responses to 1 kHz tones are similar in normal controlsubjects and tinnitus subjects before habituation training (FIG. 5),whereas the AiR responses to 4 kHz tones in normal controls and theresponses to the tinnitus frequency are in tinnitus subjects beforehabituation are very different. (N=3)

FIG. 8 is a spectrogram of a typical tinnitus habituation stimulus,showing two closely-spaced narrow band noises centered at 2800 and 3225Hz, and a very narrow band noise centered at 7417 Hz which is almost 40dB stronger than the first two.

FIG. 9 displays typical volume settings on the MPEG player used duringhabituation training.

FIG. 10 shows: at the Top, wavefonns of N100 responses to 1 kHz tonespresented at 30 dB/SL, 48 dB/SL and 54 dB/SL; and at the Bottom, N100Amplitudes plotted against stimulus intensity to show the intensitydependence function. The slope of the linear regression was used as ameasure of cortical responsiveness.

FIG. 11 is a comparison of the slopes of the intensity dependencebetween the tinnitus and control groups. A responses to 1 kHz Tones; Bresponses to 2 kHz Tones; and C responses to tinnitus frequency/4 kHzTones.

FIG. 12 shows an example of the N100 intensity dependence slope.

FIG. 13 is a representation of N100 intensity dependence slopes for the1 kHz, 2 kHz, and tinnitus/4 kHz tone in tinnitus subjects and controls.Only three midline sites (Fz, Cz, and Pz) are. shown. (p<0.05,Wilcoxon-Mann-Whitney U-Test).

DESCRIPTION OF THE PREFERRED EMBODIMENT Introduction

Based on the aforementioned modes, Inventors devised afrequency-specific or custom-made habituation stimulus that sounds likethe patient's tinnitus for habituation purposes. Such a stimulusactivates the same population of neurons affected by tinnitus. It isInventors' contention that habituation occurs when the tinnitus and thehabituating stimulus sound are as much alike as possible.

The persistent activation of cortical tissue by tinnitus is assumed tocompete for neural substrate with normal stimulus-induced activity inthe primary auditory cortex. In order to compensate, the processing ofauditory stimuli in the presence of tinnitus-related activity mayrequire an. increase in firing rate of neurons, the use of more neuralsubstrate, or a combination of both. Inventors have hypothesized thatthese compensatory mechanisms lead to an increased intensity dependencein responses to external auditory events. Since the magnitude of thelargest possible response is limited, the presence of tinnitus may leadto a steeper gain function in the responsiveness of the primary auditorycortex and a decrease in the dynamic range of hearing sensitivity.

A correlate of this steeper gain function has been reported by Norenaand colleagues [Norena, 1999], who observed an increased intensitydependence of the N100 auditory evoked potential in tinnitus subjects.The N100 is known to increase in amplitude and decrease in latency withincreasing stimulus intensity [Hillyard, 1978, Scherg, 1990, Mäkelä,1990]. This intensity dependence of the N100 response is associated withthe tangentially oriented dipole of the N100 component that is recordedprimarily along midline sites. According to studies of dipole sourceanalysis [Verkindt, 1995, Scherg, 1991], this tangentially orienteddipole reflects mainly activity of the primary auditory cortex. Incontrast, the radially oriented dipole reflects activity of thesecondary auditory cortex in the more lateral parts of the temporal lobe[Hegerl].

Since it is assumed that tinnitus-related activity involves the primaryauditory cortex, the dependent measure for this study was the midlineN100 component. This component appears to be a good index for tinnitusbecause it reflects stimulus properties as well as attention and thepsychological state of the subjects, both of which are presumed tocontribute to tinnitus [Jastreboff, 1996].

Since tinnitus perception is subjective by its very nature, there havebeen no objective measurements that could be related to it, until veryrecently [Jastreboff 1994]. A diagnosis of tinnitus has had to rely on avariety of questionnaires [Kuk 1990, Wilson 1991]. On the other hand,changes in the dynamic response characteristics of the auditory cortexby tinnitus could be used as a basis for an objective diagnostic tool.

The N100 component of the auditory evoked potential has been shown to bean indicator of activity in the central auditory system [Pritchard,1981a]; [Norena et al, 1999]; [Pineda et al, 1997; Pineda et al, 1998].Because event-related potentials like the N100 are by definition evokedby physical stimuli, whereas tinnitus is not, event-related potentialscan be used as more objective measures of tinnitus induced changes inthe processing of tones rather than the tinnitus itself [Norena et al,1999]. N100 shows reliable intensity dependence in both humans andnon-human primates [Picton et al, 1976]; [Pineda et al, 1991]. That is,as sounds get louder, the magnitude of the response increases for manyindividuals, while it decreases for others. This has been called anaugmenting/reducing (AR) response and is assumed to index the “tuning”properties of a cortical gating mechanism that regulates sensory input[Buchsbaum and Silverman, 1968]; [Lukas and Siegel, 1977]; [Pritchard etal, 1985]. Inventors' research program had two main specific aims:

1. devise an objective method for the detection of tinnitus, and

2. assess the efficacy of customized acoustic habituation therapy.

Tinnitus and Lateral Inhibition EXAMPLE I

Tinnitus Causes Specific Changes to the Augmenting/Reducing Response

As Inventors have discovered in their own laboratory and has been shownelsewhere, tinnitus increases the slope of the AR response of the N100component of the auditory evoked potential [Norena et al, 1999].Furthermore, it has also been shown by means of magnetic source imagingthat tinnitus induces tonotopically organized activity in the auditorycortex [Mühlnickel et al, 1998]. It was therefore hypothesized that theAR response at the specific frequencies at which tinnitus is perceivedwill have a steeper slope. Tinnitus patients match the pitch of theirtinnitus to the frequency of a pure tone.

The auditory evoked potential to a variety of tone pitches, includingthe tinnitus pitch, is 20 then be recorded from patients and normalcontrols. The magnitude of N100 responses allows Inventors to calculatethe slope of the AR response for tinnitus frequency tones, as well asfor frequencies not related to tinnitus perception. In normal controls,the tinnitus match is be substituted with a 4 kHz tone, since audiogramsshow a precise hearing threshold for this frequency and it is also nearthe 4.2 kHz average of tinnitus matching frequencies determined inInventors' pilot studies.

Inventors propose that the observed increase in the slope of the AR intinnitus is due to tinnitus-related activity present in the auditorycortex. It is their contention that this activity interferes withstimulus driven activity in such a way that more cortical tissue has tobe activated and that firing rates of individual cortical neurons haveto be higher in order to allow for processing of peripheral stimuli.This increased activation of the auditory cortex manifests itselfas anincreased slope of the AR. Plastic changes mediated by a positivefeedback loop involving structures in the limbic system and mechanismsof lateral inhibition in the auditory pathway may lead to themaintenance of the tinnitus experience. This line of argumentation linksthe thalamic model of Jeanmonod [Jeanmonod et al, 1996], which forms thebasis for the proposal, and the changes in inventors' dependentvariable.

The first step towards a characterization of the augmenting/reducingresponse was to develop a method that allowed Inventors to reliablyrecord the N100 component and separate it from background noise. Thesize of the N100 component is largely determined by the loudness of thestimulus. Since Inventors anticipated working with subjects that havesome degree of hearing loss, they chose to use stimulus volume settingsthat correspond to the subjects' individual hearing thresholds ratherthan use the same predetermined volume settings for all subjects. Thischoice of volume settings should ensure that the perceived loudness ofthe stimuli is as similar as possible across subjects. If the stimulusis presented at 30 dB or more above the subject's hearing threshold atthe stimulus frequency, the signal-to-noise ratio is sufficient toreliably detect the N100 component and to demonstrate it's dependence onstimulus intensity (FIG. 3).

Another factor that affects the ability to detect the N100 component isthe placement of the reference electrodes. We, therefore, recorded theauditory evoked potentials comparing a number of different references,including a single mastoid, linked mastoid and the average referencemethod [Katznelson, 1981]. The results showed that the N100 componentand the entire N100/P200 complex was seen most clearly using the linkedmastoids as a reference. The recordings made with the linked mastoidsreference is also the only one in which the wave form of the N100/P200complex closely resembles the waveforms found in previous publications,e.g. [Picton et al, 1976] (FIG. 4). Because the N100/P200 complex waspresent at various electrodes, re-referencing the single mastoidrecordings to the average potential of all electrodes partiallycancelled the N100/P200 signal, worsening the signal-to-noise ratio.

In another study, Inventors asked tinnitus subjects to match the pitchof their tinnitus to the frequency of a sine tone and recorded theirauditory event-related potentials to tones of this frequency at 30 dB,36 dB, 42 dB, 48 dB, and 54 dB above their individual hearingthresholds. The N100 amplitude in response to these tinnitus frequencytones showed a much larger intensity dependence than to 1 kHz tones.Likewise, N100 latencies increased with increasing stimulus volume (FIG.5).

The responses to 2 kHz and 4 kHz (chosen to substitute for the tinnitusfrequency) tones were recorded from normal listeners in two separatecontrol experiments (FIG. 6 and FIG. 7). In the control subjects, theresponses to 1 kHz tones were much more strongly intensity dependentthan responses to 4 kHz tones, while the N100 latency to the 4 kHz tonesdecreased with increasing stimulus volume. Taken together these findingsstrongly suggest that tinnitus induces specific changes to theaugmenting/reducing response.

Materials and Methods Subjects

Eight subjects suffering from tinnitus (mean age: 46.8 yr.; S.D.=±11.7)and twelve control subjects (mean age: 39.1 yr.; S.D.=±10.7) werestudied. The hearing thresholds of all subjects were determined; usingroutine pure tone audiometry. Patients suffering from tinnitus werereferred from the Head and Neck Surgery Clinic at the UCSD MedicalCenter, while control subjects were recruited from the population of theUCSD campus. An effort was made to match the age of the control subjectsto the age of the tinnitus subjects. Informed consent was obtained fromall subjects. The Institutional Review Board of the University ofCalifomia, San Diego approved the experimental procedures.

Tinnitus Matching Procedure

A subject's tinnitus perception was characterized prior to everyrecording session by matching the pitch of their tinnitus to thefrequency of a sine tone. In our experience, this matching procedure hasproven vulnerable to octave confusions, i.e. some subjects matched theirtinnitus pitch consistently at two different frequencies, depending onwhether the matching procedure was begun at a frequency higher or lowerthan their tinnitus pitch. These frequencies generally were one or twooctaves apart. If this was the case, we alternately presented bothfrequencies to the subject and asked which one was a better match.

EEG Experiments

EEG was collected using standard methods. Data were recorded from 15electrode sites mounted on an elastic cap and located over the followingscalp sites: F3, Fz, F4, C3, Cz, C4, P3, Pz, P4, T3, T4, T5, T6, O1, andO2 (according to the modified International 10-20 System). Eye movementartifact, particularly blinks, was recorded from vertical and/orhorizontal EOG electrodes. In order to maintain compatibility withprevious studie, all electrode sites were referred to linked mastoids.Within each series, 80 stimuli of different intensities, for a total of400 stimuli, were presented. in random order and at intervals varyingrandomly between 1 and 3 sec. The EEG was amplified by a factor of10,000 and bandpass filtered between 0.01 to 100 Hz using 3 dB downfilter skirts. Analog signals were recorded and digitized at a samplingrate of 250 Hz.

The auditory stimuli were pure tones generated by a function generator.A specially designed programmable logarithmic amplifier that wascontrolled in real time by a stimulus presentation and data collectionprogram set the intensity of each stimulus. Tone pips of 200 ms durationwere presented at five different intensities (30 dB SL, 36 dB SL, 42 dBSL, 48 dB SL and 54 dB SL) through insert earphones (Eartone 3Atransducers with Earlink foam eartips). Inventors recorded auditoryevent-related potentials (ERP) in response to tones at threefrequencies. For the tinnitus subjects these frequencies were 1 kHz, 2kHz and their tinnitus-match frequency. In non-tinnitus subjects 4 kHzsubstituted for the tinnitus frequency.

Data Analysis

The EEG data were analyzed using a two-stage approach. In the firststage, traditional artifact rejection was employed to remove trials withamplifier blocking and those that contained eye movement artifacts. Theartifact-free EEG epochs for each intensity and condition were thenaveraged and the amplitudes of the N100 components measured. Based onthese data, intensity-amplitude functions were computed for all 15electrode sites. These were used to characterize an individual'sresponsiveness to specific tonal frequencies.

The peak amplitudes of the N100 component were measured and plottedagainst the stimulus intensity. A linear regression was calculated, andits slope was used to characterize the intensity dependence of the N100component recorded from the midline electrode sites Fz, Cz and Pz. Foreach stimulus frequency, these intensity-amplitude functions werecompared between the tinnitus and control groups using a 2-tailedWilcoxon-Mann Whitney U-test (p<0.05). Since three tests were performedfor each stimulus condition, a correction for multiple comparisons basedon the binomial distribution [Bortz, 1990] was performed by calculatingα′: $\alpha^{\prime} = {\sum\limits_{i = n}^{k}\quad{\begin{pmatrix}k \\i\end{pmatrix}{\alpha^{i} \cdot \left( {1 - \alpha} \right)^{k - i}}}}$where k was the number of tests performed, n the number of tests thatshowed a significant result and a the significance level of theindividual tests. Differences in the intensity-amplitude functions wereconsidered significant when α′ was less than the desired significancelevel, i.e. α′<0.05.

Results

The results of the audiometric testing are shown in Table 1. An exampleof the N100 waveforms and its intensity-amplitude function is shown inFIG. 1. Comparison of the slopes of the intensity-amplitude functionsbetween the tinnitus and control groups showed that the N100 responsesfrom tinnitus patients to tones at their tinnitus frequency wereslightly more intensity dependent (i.e.,. steeper slopes) than those ofnon-tinnitus controls to 4 kHz tones (FIG. 2C). In contrast, responsesfrom the tinnitus group were significantly (p<0.05) less intensitydependent to 2 kHz tones than responses from the non-tinnitus controlsubjects (FIG. 2B). The intensity dependence of responses to 1 kHz tonesis.nearly identical in tinnitus and control subjects (FIG. 2A). Takentogether these findings strongly suggest that tinnitus induces specificchanges to N100 intensity dependence.

Discussion

The present results support the hypothesis that the presence of tinnitusrelated activity changes the intensity dependence of the N100 in afrequency TABLE 1 Hear- ing Right Left loss 1 kHz 2 kHz 4 kHz 1 kHz 2kHz 4 kHz Tinnitus Wnl 7 6 4 8 7 3 Mild 1 1 1 0 1 5 Mod 0 1 3 0 0 0Control Wnl 12 12 10 12 12 11 Mild 0 0 1 0 0 1 Mod 0 0 1 0 0 0Abbreviations: Wnl: Within normal limits; Mod: Moderatespecific manner. The experimental data show statistically significantreductions in the intensity dependence of the N100 in response to 2 kHztones and a non- significant increase in the intensity dependence ofresponses to the tinnitus frequency tones (4 kHz tones). It isInventors' contention that tinnitus related activity produces anincrease in firing rate of neurons or activation of more neuralsubstrate. This, we believe, is reflected in the enhanced intensitydependence to. tones at that frequency. Furthermore, enhanced activationof this isofrequency region causes inhibition of neighboring regions vialateral inhibitory mechanisms. This is reflected in the reducedintensity dependence to neighboring tones.

Inventors' working model of tinnitus is drawn from a recently proposedneurophysiological model of the disorder [Jeanmonod, 1996] in whichtinnitus arises as a consequence of thalamocortical dysrhythmias. Moreprecisely, auditory nuclei in the thalamus interact to establish areverberating loop in which neuronal activity originating from thisreverberating loop gets transmitted to the auditory cortex, where itgives rise to the perception of tinnitus. Such reverberating loops areestablished through disinhibition of cells in the thalamus, which occurswhen thalamic relay cells are hyperpolarized by a lack of normaldepolarizing sensory input. The action potentials generated by thishyperpolarizing mechanism, or low threshold spikes (LTS), usually occurin rhythmic bursts.

A computational model of tinnitus recently proposed by Langner et al.[Langner, 1999] accounts for how a decreased auditory input resultingfrom a peripheral hearing deficit can give rise to a specific tinnituspitch. According to this model, the detection of tinnitus-relatedactivity is facilitated by mechanisms of lateral inhibition in thecentral auditory system. These act to confine the neural activitycausing the phantom perception to regions representing distinctfrequencies and increase the contrast between the tinnitus-relatedactivity and the spontaneous activity in adjacent regions.

Another indication that tinnitus related activity is confined to certainisofrequency regions of the auditory cortex comes from the fact thatmost tinnitus perceptions have distinct pitch. Furthermore, this pitchis often related to the underlying pathology. For example, noise-inducedtinnitus tends to have a pitch near 4 kHz [Mitchell, 1984]. In caseswhere the tinnitus is perceived as tonal, tinnitus-related activity inthe auditory cortex can be assumed to be limited to isofrequency regionsthat correspond to the tinnitus pitch. Consequently, the changes in theintensity dependence of the midline auditory N100 response can beexpected to be frequency specific.

Based on these models, a likely explanation for Inventors' findings isthat tinnitus-related activity in the 4 kHz isofrequency region givesrise to lateral inhibition and thereby inhibits responses from theadjoining 2 kHz isofrequency region of the primary auditory cortex. Thisproduces decreased intensity dependence of the auditory evoked potentialin response to 2 kHz tones. This lateral inhibition effect must belimited in range such that responses to tones that are sufficientlydifferent from the tinnitus frequency are not affected. Indeed, theintensity dependence of responses to 1 kHz tones is nearly the same intinnitus and control subjects. This last finding contrasts with theincreased intensity. dependence of the N1/P2 component reported byNorena et al. However, since the N1/P2 complex is thought to begenerated by equivalent dipoles representing the primary and secondaryauditory cortices, whereas the N100 observed in this study is thought tobe generated by equivalent dipoles representing only the primaryauditory cortex, the contribution of the secondary auditory cortex maycontribute to the higher intensity dependence observed by Norena et al.Another factor that can be expected to influence the intensitydependence of the N100 is hearing loss. As shown in Table 1, about halfof the tinnitus subjects had some hearing loss at their tinnitusfrequency. This hearing loss could lead to recruitment, i.e. increasedloudness growth in response to higher intensity stimuli. Recruitment maybe an alternative explanation for the increased intensity dependence ofthe N100 response at the tinnitus frequency. However, hearing for thetinnitus subjects was less impaired at 2 kHz, i.e. an octave lower thanthe tinnitus, so that hearing loss cannot account for the changeddynamics in N100 responses to these tones. Furthermore, the effect ofhearing loss, as described above would be to cause an increase of theN100 intensity dependence rather than the observed decrease.

Conclusions

The present results suggest that tinnitus related activity in theprimary auditory cortex changes the characteristics of the N100component of the auditory evoked potential in a frequency specificmanner. In tinnitus subjects responses to tinnitus frequency tones areslightly more dependent on stimulus intensity than in controls, whileresponses to 2 kHz tones, i.e. approximately one octave below thetinnitus frequency are significantly less dependent on stimulusintensity. The lack of intensity dependence in responses to 2 kHz tonesis most likely caused by lateral inhibition in the auditory cortexarising from the tinnitus related activity. The observed changes in thedynamic properties of the N100 response is a way of demonstratingtinnitus related activity in the central neural system and may providethe basis for an objective. tinnitus diagnostic tool.

EXAMPLE II Habituation Therapy

Procedures

Subject evaluation.

Two groups of subjects are selected and evaluated: normal controls andsubjects with tinnitus. They are evaluated initially to determinehearing thresholds, as well as tinnitus pitch and intensity levels. Theaudiologist technician conduct s these procedures. Subjects areinitially screened at the Otolaryngology Clinic to ensure they have noserious physical or mental disorders, have no other auditory deficits,and do not take any medication or other substances, which may affect EEGrecording. Care is taken to ensure a balance between male and femalesubjects. Group sizes according to study design.

Pure Tone Audiometry Procedure

Prior to ERP experiments or habituation therapy, all subjects will havetheir audiogram taken using standard clinical procedures. For tinnitussubjects the audiogram are repeated every 3 months during habituationtherapy and after completing the habituation therapy.

Subjective Tinnitus Pitch/Intensity Determination

A subject's perception of his or her tinnitus is characterized prior toevery recording session by matching the pitch of their tinnitus to thefrequency of a sine tone and the loudness of their tinnitus to thevolume of a sine tone that matches the pitch of the tinnitus.

The following constitute typical instructions given to the subjects:“You are going to match a tone presented through the earphone or thespeaker to the tone of your tinnitus for pitch/loudness. Every time thatthis tone is presented, I want you to compare it to your tinnitus toneand report that the presented tone is either:

“higher in pitch/loudness than your own tinnitus tone, equal to your owntinnitus tone, or

lower in pitch/loudness to your own tinnitus tone”

In Inventors' experience matching the pitch of the tinnitus to thefrequency of a sine tone has proven to be vulnerable to octaveconfusions, i.e. the tinnitus subjects match their tinnitus pitchconsistently at two different frequencies, depending'on whether thematching procedure was begun at a frequency higher or lower than theirtinnitus pitch. These frequencies are usually roughly one or roughly twooctaves apart. If this is the case, Inventors present both tones to thesubject and ask which one is a better match.

Tinnitus Masking Level Determination

The tinnitus masking level is the level of the external stimulus tonethat masks the tinnitus, according to the subject. This should be alevel just above the reported tinnitus intensity level. Stimulus tonesare initially presented at an intensity level below the determinedintensity level of the tinnitus (this could even be at HL-5dB). Subjectsare given instructions similar to those described previously. Forexample, “you are going to tell me when you can no longer hear your owntinnitus. Every time that a stimulus tone is presented at a certainloudness, I want you to make a decision as to what you hear and report:

“I hear my tinnitus only”.

“I hear both the stimulus tone and my tinnitus”.

“I hear the stimulus tone only”.

The masking level is the lowest intensity at which the subject reportsthat they only hear the stimulus tone. The procedure is repeated once ortwice for reliability.

EEG Procedures

In order to detect tinnitus-related changes in the processing ofauditory stimuli in the central auditory system, the auditory evokedpotential is recorded. This involves the recording and analysis of EEGand ERPs. EEG is collected using standard methods. Data are recordedfrom 15 electrode sites mounted on an elastic cap and located over avariety of scalp sites (F3, Fz, F4, C3, Cz, C4, P3, Pz, P4, T3, T4, T5,T6, O1, and O2 according to the modified International 10-20 System).Eye movement artifacts, particularly blinks, are recorded from verticaland/or horizontal EOG electrodes. In order to maintain backwardcompatibility with previous studies, e.g. [Norena et al, 1999], andbecause Inventors' preliminary experiments show that the N100/P200complex is best seen with referencing to linked mastoids, all electrodesites are referred to linked mastoids. Within each series, 80 stimuli ofdifferent intensities, for a total of 400 stimuli, are presented inrandom order and at intervals varying randomly between 1 and 3 sec.

Inventors are aware that a better signal to noise ratio would beachieved with more stimulus presentations. However, for the purposes ofthis study, their preliminary experiments show the signal-to-noise ratioto be sufficient (see FIG. 4).

The EEG is amplified by 10K and bandpass filtered between 0.01 to 100 Hzat 3 dB down. Analog signals are recorded and digitized at a samplingrate of 250 Hz. For stimulus presentation and data acquisition andanalysis, the ADAPT scientific software ((c) A.Vankov, 1997) orNeuroscan software is used. Both of these software packages permit thedelivery of complex stimulus patterns and simultaneous data collectionand analysis.

Auditory Stimulation

The auditory stimulations are sine waves generated by a functiongenerator (Goldstar FG2002C). The intensity and the duration of eachstimulus are set by a specially designed programmable.logarithmicamplifier that is controlled in real time by a stimulus presentation anddata collection program running in ADAPT. Auditory stimuli of fivedifferent intensities are presented through insert earphones (Eartone 3Atransducers with Earl link foam eartips). In one stimulation series, thetone frequency is the subjectively assessed frequency of the subject'stinnitus. Three more stimulation series with stimulus frequencies at 1kHz, 2 kHz and 8 kHz are carried out. In all series, tones are of 200 msduration and varying in intensity (+30 dB, +36 dB, +42 dB, +48 dB, and+54 dB above the subject's hearing threshold at that frequency). Fornormal controls the auditory stimulation consists of series using I kHz,2 kHz, 4 kHz, and 8 kHz, i.e. the stimulation series using the tones ofthe tinnitus frequency is substituted by one using 4 kHz tones.

Experimental Paradigm

On the day of testing, the sequence of the procedures is as follows:

1. In tinnitus subjects: Determine the “matching frequency” (pitch) ofthe subject's tinnitus. Subjects are presented with a continuous,audible tone varying in pitch. They are asked to indicate the frequencythat most closely matches the frequency of their tinnitus. Several runsare used to determine the mean of the reported frequencies. Pitchmatching is done in audiometrics.

2. In tinnitus subjects: Determine the hearing threshold for thetinnitus frequency. Subjects are presented with a continuous tone thatgradually increases in volume. They are asked to indicate when theybegin to hear the tone. The intensity at which the subjects begin tohear the tone is considered the hearing threshold (0 db). For EEGrecording, tones at the tinnitus frequency are presented at volumes 30dB, 36, dB, 42 dB, 48 dB, and 54 dB above this hearing threshold.Several runs are used to determine the subject's hearing threshold.

3. In tinnitus subjects: Determine the “matching intensity” of thesubject's tinnitus. Subjects are presented with a continuous tone thatincreases or decreases in volume. They are asked to indicate the momentwhen they perceive the tone as being of the same loudness as theirtinnitus. Several runs are used to determine the mean of the reportedintensities. Masking level is determined in audiometrics.

4. Determine the hearing threshold for the “off” frequencies. The sameprocedure as in (2) is used, but with 1 kHz, 2 kHz, and 8 kHz tones (incontrol subjects: 1 kHz, 2 kHz, 4 kHz, and 8 kHz tones). For EEGrecording, these tones are presented at volumes 30 dB, 36, dB, 42 dB, 48dB, and 54 dB above this hearing threshold.

Following the determination of the tinnitus pitch and intensity andsubject's hearing threshold, one series of tonal stimulation and EEGcollection takes place at each stimulus frequency. The series arepresented in random order determined with a dice.

EEG Data Analysis

In one embodiment, the EEG data are analyzed using a two-stage approach.In the first stage, they are artifact-rejected. Initially, traditionalartifact rejection is employed to remove trials with amplifier blockingand those that contain eye blinks. In the second stage, the remainingsingle trials are concatenated and submitted to an ICA decomposition.Components that account for eye, muscle, or movement artifacts areselected and those rows in the activation matrix are set to zero. Thedata are then reconstructed without the artifacts (for a detaileddescription of the ICA algorithm and how it is applied to correct forEEG artifact, see [Makeig et al, 1997]; [Makeig et al, 1999]). Theartifact-free EEG epochs for each intensity and condition are averagedand the amplitudes of the N100 components measured. Based on these data,intensity-amplitude functions are computed for all 15-electrode sites.These are used to characterize an individual's responsiveness tospecific tonal frequencies and as the measure of changes in thatresponsiveness.

EXAMPLE II EEG Index of Tinnitus

Inventors determined whether N100 intensity dependence (i.e., thechanges in amplitude in this brain signal as a finction of stimulusintensity) differs in tinnitus sufferers compared to non-tinnituscontrol subjects. The experiment thus far has involved 24 tinnitussubjects and 14 control subjects. Tinnitus subjects were initially askedto match the pitch of their internal tinnitus to the frequency of a sinetone.

Auditory ERPs in response to tones of up to four frequencies wererecorded. For the non-tinnitus control subjects, these frequencies were1 kHz, 2 kHz, 4 kHz and 8 kHz. In tinnitus subjects, their own tinnitusfrequency was substituted for one of the frequencies used with thecontrol subjects. For all subjects, tone pips were presented atintensities of 30 dB SL, 36 dB SL, 42 dB SL, 48 dB SL and 54 dB SL. Thepeak amplitudes of the N100 component were then measured and plotted asa function of stimulus intensity. A linear regression was calculated,and its slope used to characterize the intensity dependence of the N100component (see FIG. 12).

The resulting data from a subset of the tinnitus group, i.e., thosesubjects whose tinnitus pitch was near 4 kHz, show significantly higherintensity dependence of the N100 compared to controls (see FIG. 13).Furthermore, comparison of the N100 intensity dependence of the tinnitusand control subjects showed that the N100 responses from tinnituspatients to 2 kHz tones was significantly less intensity dependent(i.e., smaller slopes) than those of non tinnitus controls(Wilcoxon-Mann-Whitney U-test, p<0.05). In contrast, responses from thetinnitus group were slightly more intensity dependent to their tinnitusfrequency tones (which had a mean of 4.2 kHz) than responses to the 4kHz from the non-tinnitus control subjects.

Audiograms were taken from all of the tinnitus subjects and 11 of thecontrol subjects. Two of the tinnitus subjects had mild and one hadmoderate hearing loss at their tinnitus frequency. The hearing lossobserved at the tinnitus 15 frequency makes it possible that thestronger intensity dependence observed in the responses of tinnituspatients to tinnitus frequency tones may have been caused by recruitment(abnormal loudness growth) rather than tinnitus. However, the weakerintensity dependence observed in responses to 2 kHz tones is opposite ofthe effect of recruitment, and thus not attributed to it. Inventorsattribute this effect on intensity dependence to the lateral inhibitioncaused by the tinnitus-related activity in the auditory cortex.

EXAMPLE III Customized Habituation Therapy with Habituation Stimuli

Although their judgements are necessarily subjective, tinnitus subjectshave evinced excellent consistency when it comes to matching habituationsounds with their tinnitus. Before beginning the habituation therapy,Inventors required subjects to confirm that the habituation soundmatched their tinnitus at two or more sessions separated by at least aweek. While there is some evidence that adjustments in the habituationstimulus may be desirable after habituation has progressed a few weeks,it seems reasonably clear, that this is due to changes in thecharacteristics of the tinnitus itself rather than a mismatch in thehabituation sounds. The frequency content of a typical habituationstimulus is shown in FIG. 8.

Tinnitus retraining therapy requires habituation to constant noiseexposure. In order for habituation to occur, the habituation stimulushas to be audible, but must not be so loud as to mask the tinnitus[Jastreboff et al, 1996]. Therefore, the volume setting that a tinnitussubject uses on their noise generator gives an estimate of the loudnessof the tinnitus. The volume settings that Inventors' tinnitus subjectsused during this experiment decreased over time, in one case so muchthat the subject exhausted the available volume settings and thestimulus had to be resynthesized at a lower intensity (FIG. 9).

Since the experimental recording procedure required a determination ofthe hearing threshold every time a recording of an auditory evokedpotential was made, Inventors have records of the changes to the hearingthresholds during habituation therapy. Hence, in a typical recordingsession, subjects had their hearing threshold determined and auditoryevoked potentials recorded at their tinnitus frequency and at 1 kHz.Subjects then listened to their customized habituation stimulus for anhour and the determination of the hearing thresholds and the recordingof the auditory evoked potential was repeated. Within a session, thehearing threshold at the tinnitus frequency was lowered by as much as 15dB. Over several weeks of habituation training, hearing thresholds atthe tinnitus frequency were observed to decrease by as much as 25 dB(FIG. 10).

Habituation training caused changes in the intensity dependence of theN100 amplitude as well as N100 latencies oftinnitus subjects. Beforeexposure to customized habituation stimulus the amplitude of the N100component of the response to a tinnitus frequency tone was much moreintensity dependent than the N100 component in response to a 1 kHz tone.Likewise, the N100 latencies increased with increasing stimulus volume.After subjects listened to the habituating stimulus for one hour, theintensity dependence of the response to the 1 kHz tone increased, andthe latency of the N100 component of the response to the tinnitusfrequency tone decreased with increasing stimulus volume (FIG. 5).Normal hearing control subjects were exposed to a stimulus similar tothe habituating one for the tinnitus patients. The stimulus used inthese control experiments was a narrow noise band with a centerfrequency of 4 kHz. Neither the intensity dependence of N100 amplitudeor latency were changed by the exposure to the control stimulus (FIG.6). Taken together, these findings suggest that the exposure to thehabituating stimulus has an effect on tinnitus related activity in theauditory cortex. of the tinnitus subjects. A single one-hour exposure,however, is not enough to make the pattern of intensity dependencesimilar to the one observed in normal controls.

Habituation training in conjunction with directive counseling has beenshown to be an effective treatment for tinnitus [Jastreboff et al,1996b]. Typically, white noise is used as the habituating stimulus intinnitus retraining therapy (TRT). White noise evokes stimulus-inducedneural activity in all of the parallel frequency-specific channels inthe auditory system and is therefore likely to cause activity in thosepopulations of neurons that also show tinnitus-induced activity. Forhabituation training, it may be sufficient to excite a much smallerpopulation of neurons, namely those that are contributing to thetinnitus. A physical stimulus targeting these neurons would induce asimilar perception as the tinnitus, i.e. sound like the tinnitus.Inventors propose to synthesize stimuli to match the patient's tinnitusand use this sound for habituation training. By recording the patient'sauditory evoked potentials, Inventors can quantitatively describe thechanges in the electrophysiological markers induced by the habituation.Further, Inventors will record the changes in audiometric tests as wellas in subjective tinnitus measures.

Habituation therapy as proposed by Jastreboff [Jastreboff et al, 1996b]has been shown to achieve an 84% success rate in patients in terms ofdecreased annoyance induced by tinnitus and showing clear habituation ofits perception.

Jastreboff claims that habituation therapy using white noise as ahabituation stimulus causes the signal-to-noise ratio between thetinnitus related activity and spontaneous activity in the centralauditory system to decrease. At the same time, the central auditorysystem undergoes a habituation to the permanent presence of an auditorystimulus. This habituation should lead to a decrease in tinnitus-relatedactivity and consequently to decreased tinnitus perception andannoyance. However, descriptions of tinnitus perception and Inventors'preliminary results indicate that the tinnitus perception and theperception caused by white noise are very different from each other.When white noise is used for habituation therapy, two distinctcontinuous auditory perceptions are present. One is the behaviorallyirrelevant, stimulus-driven perception of the white noise, the other isthe tinnitus, a highly annoying phantom perception. In these conditions,habituation is likely to occur, but it is habituation to white noiserather than to the tinnitus perception.

Inventors' approach is designed to produce a habituation to the tinnitussound, by making the perceptions of the tinnitus sound and thehabituating stimulus as similar as they can possibly be. This is done byusing a customized sound that mimics the tinnitus perception as ahabituation stimulus.

Thus, the perceptions experienced by Inventors' subjects are verysimilar, allowing the habituation to the customized habituation stimulusto extend to the tinnitus. In this part of the study Inventors testwhether this approach is an effective treatment of tinnitus, i.e. causestinnitus related annoyance to disappear, and whether theelectrophysiological correlates of tinnitus described in Example I arechanged as a consequence of this treatment.

Subjective Tinnitus Pitch/Intensity Determination

The subjective experiences of tinnitus are characterized by Dr. Mooreusing a successive approximation technique. Individual subjects areasked to verbally describe to a sound synthesis expert the “sounds” theyexperience using whatever vocabulary they possess for describing sounds.Musical training and experience on the part of the subject areparticularly valuable in this process, since they provide a usefullanguage in which sound characteristics can be verbally communicated.However, while musical training or experience is helpful, they are notnecessary in order to achieve good and consistent tinnitus match. Inresponse to the subject's statements, sounds are synthesized usinghigh-precision, general-purpose sound synthesis software. At present Dr.Moore synthesizes the tinnitus sound according to the descriptionprovided by the subjects using the program “pcmusic” (see for example[Moore, 1990]). The resulting sound is then played back to the subject,who responds with suggested adjustments, such as altering the pitch,number of components, balance or quality of the synthetic sound. Inresponse to these suggestions, the sound description file is modified,and the process is repeated until the subject reports that thesynthesized sound matches well his or her subjective tinnitusexperience. The digitized sound is then downloaded into a small portabledigital sound playback device (MPEG-player) for use during habituation.The synthesized sound is completely documented by the description filetogether with the pcmusic program, as well as any number of post factotechniques, such as Fourier analysis. The time needed for thissuccessive approximation procedure can vary, depending on the subject'sability to describe their own subjective experience of tinnitus, andtheir ability to characterize differences between the tinnitus theyexperience and the sounds being synthesized by the computer. Practicalexperience indicates that this can be done in about two or three 2-hoursessions devoted to accurately characterizing the subject's experience.

Tinnitus Masking Level Determination

Determination of the tinnitus masking level is the same as in Example I.

EEG Procedures

EEG Procedures are the same as in Example I.

Auditory Stimulation

The auditory stimulation is similar to that used in Example I. Since the1 kHz and tinnitus frequency tone are presented before and afterhabituation (see ‘Experimental Paradigm’ below), the 2 kHz and 8 kHztones are not presented.

Experimental Paradigm

On the day of testing, the sequence of the procedures is as follows:

Determine the “matchingfrequency” (pitch) of the subject's tinnitus.

Subjects are presented with a continuous, audible tone varying in pitch

They are asked to indicate the frequency that most closely matches thefrequency of their tinnitus. Several runs are used to determine the meanof the reported frequencies.

Determine the Hearing Thresholdfor the Tinnitus Frequency

Subjects are presented with a continuous tone that will graduallyincrease in volume. They are asked to indicate when they begin to hearthe tone. The intensity at which the subjects begin to hear the tone isconsidered the hearing threshold (0 db). For EEG recording, tones at thetinnitus frequency are presented at volumes 30 dB, 36, dB, 42 dB, 48 dB,and 54 dB above this hearing threshold. Several runs are used. todetermine the subject's hearing threshold

Determine the “matching intensity” of the Subject's Tinnitus

Subjects are presented with a continuous tone that will increase ordecrease in volume. They are asked to indicate the moment when theyperceive the tone as being of the same loudness as their tinnitus.Several runs are used to determine the mean of the reported intensities.

Determine the hearing threshold for the “off” frequency. The same.procedure as above is used,. but with a 1 kHi tone. For EEG recording,.1 kHz tones are presented at volumes 30 dB, 36, dB, 42 dB, 48 dB, and 54dB above this hearing threshold.

Following the determination of the tinnitus pitch and intensity andsubject's hearing threshold two series of tonal stimulation and EEGcollection will take place. The first series is at the tinnitusfrequency, while the second one is at the “off” tonal frequency (1 kHz).

At the end of the tonal series, subjects are exposed to 1-hr ofhabituation with customized habituation sound. The subjective “masking”threshold of the tinnitus is determined. They will then listen to thesound at 6 dB below the masking threshold for approximately 1 hour. Thehearing. threshold at the tinnitus frequency and at the “off” frequencyis measured again at the end of the one-hour habituation. At the end ofthe habituation period and after a 2-minute break, two more series oftonal stimulation and EEG collection, identical to the ones describedabove, are conducted.

Subjects are given the MP3 player with the habituation stimulus andasked to listen to it for as long as it is comfortable each day They areasked to return to the lab after one, four, and 12 weeks of habituationtherapy for the same EEG evaluation.

Data Analysis

The EEG data are analyzed using the procedures described in Example I.When the slopes of the augmenting/reducing responses are calculated,Inventors look for changes within and between sessions. These. changesare correlated to the. behavioral data obtained during the experimentalsessions.

Habituation therapy using white noise leads to an improvement in 83% ofcases [Jastreboffet al, 1996b]. Therefore, an important question to beaddressed in this aim is not only whether successful tinnitus treatmentreturns behavioral and EEG indices to normal or whether one type oftherapy is faster than another but whether these parameters havepredictive value in terms of treatment efficacy. This data analysis willalso involve an analysis of all the data collected for Example I inorder to develop a model that can make reasonable inferences and serveas a diagnostic tool to monitor habituation therapy. If there is aspecific pattern of alteration, clinicians will have a reliable tool tohelp assess the effectiveness of these acoustic therapies.

Subject Populations

Approximately 200 normal, healthy, ethnically diverse adults (aged18-30), both male and female, who are recruited from the general studentpopulation at UCSD are studied each year. The population at UCSD isapproximately 48% male and 52% female. The breakdown in terms ofethnicity is Caucasian (39%), Asian (30%), Mexican-American (8%),Filipino (5%), others (18%).

Subjects are recruited through bulletin board ads, email, announcementsin undergraduate courses, and personal references They are paid fortheir participation in the experiments on an hourly basis or compensatedwith credit toward undergraduate coursework. They are asked to read andsign a consent form approved by the Institutional Review Board (IRB).Subjects are made aware of the risks, which are minimal since all thehardware has been designed for this particular purpose, the stimuli areof low intensity and painless, and the subjects are not be placed underany stress. Any discomfort due to the skin abrasion and electrode gelmay remain for a short while after the experiment is completed

EXAMPLE IV Altered Cortical Responses in Tinnitus Patients FollowingHabituation Therapy

Inventors examined short and long term effects of habituation to acustomized sound. Habituation to a customized sound may have effects atboth a behavioral and an electrophysiological level. Patients descnbethe effect of listening to their customized sound as comforting, sayingfor example that it helps them fall asleep or make them feel in controlof their tinnitus. Patients give this feedback frequently within minutesafter first turning on their MP3 players. In order to substantiate thesepatient testimonials, patients were asked to complete the TinnitusHandicap Questionnaire before and after the three week habituationperiod. The questionnaire consists of 27 statements. to which thepatient responds by writing down a number between 0 and 100 next to eachstatement, where 100 means complete agreement and 0 completedisagreement with the statement. The questionnaire is constructed insuch a way that high scores indicate more severe tinnitus. than lowscores. The questionnaire assesses the overall effect tinnitus has onthe patient's life. It contains three subscales that measure the effectstinnitus has on more specific aspects of a patients life, namely theirmental health, their ability to hear and their attitude. towardstinnitus. So far three patients have. completed the. three weekhabituation protocol, giving the following scores: TABLE 2 OverallMental Health Hearing Attitude before 11.2 17.9 5.0 5.0 after 5.6 5.71.7 5.0 before 50.0 67.9 29.2 37.5 after 37.0 53.2 23.3 27.5 before 48.868.6 23.3 40.0 after 48.0 64.3 37.5 25.0

Another way of assessing the effectiveness of the Customized Soundtherapy is by observing. the EEG correlate of tinnitus. We undertook aseries of EEG experiments in which we measured the change of theintensity dependence of the amplitude and latency ofthe auditory N100response as a consequence ofone hour. of habituation training. Werecorded the responses to tinnitus frequency tones and 1 kHz tones fromtinnitus patients and control subjects before and after one hour ofhabituation. Tinnitus patients used their customized sound forhabituation, control subjects used narrowband noise with a centerfrequency of 4 kHz, and 4kHz tones were presented to substitute for thetinnitus frequency. Due to the small number of subjects in this studythe results of these experiments do not reach statistical significance.However the provide an indication that the response pattern of tinnituspatients was changed by one hour of habituation (FIG. 5), while no sucheffect was observed in the control subjects (FIG. 6).

EXAMPLE V Automatic Feedback Habituation System

A flow diagram representing the steps involved is seen in FIG. 11. Fromthis diagram, the novelty of the invention is clearly apparent. Subjectscome to a PC workstation with electronic sound players. Softwaredesigned by an electronic sound expert presents a series of tones to thesubjects and refines them to match the subjects' tinnitus experiencethrough a series of controllers that the subjects will manipulatethemselves. An electronic recording of the sound is then made in adigital music format, typically MP3 that is then stored on the computer.A. copy of the electronic sound file is then transferred to theelectronic music player. This device is solid state electronics thatstores and plays back music through a set of attached headphones.

After the customized sound generation, an EEG signature of a subject'sbrain activity is generated. The customized sound is used to stimulatethe auditory system while the brain activity is recorded. The subject'sresponse to sounds not corresponding to their tinnitus signature isrecorded, as well as their brain activity during the absence of soundstimuli. The EEG responses to sound stimuli and to the absence of soundare downloaded into the controlling computer. While the EEG is activelybeing monitored by the computer, it generates the customized sound. EEGsignature for tinnitus is monitored as well as the signature forsilence. Periodically, the signatures for tinnitus and silence aretested for and the controlling computer determines if the tinnitus isgoing down and the silence signal is strengthening. If these changes arenot present, the computer slightly alters the sound stimuli and againchecks for feedback that the appropriate changes are being seen. Thecomputer continuously monitors for the feedback signatures and drivesthe sound stimuli appropriately.

The method of using brain signals to drive the sound generation forsuppression of tinnitus is unique. Inventors assert that this method canlikely be generalizable to a wide variety of medical conditions whereinput signals can be used to suppress brain activity and be maximized bybrain signal feedback. For example, brain signatures for motionsensation and absence of motion could be used with visual motiongeneration to reduce chronic vertigo. Moreover, Parkinson's diseasecould suppressed by motor control stimuli and motor signal feedback, ordepression could be suppressed by visual and auditory stimuli drivenwith EEG signature feedback.

The potential clinical application for this is the rapid treatment oftinnitus. Currently there are sound therapies for tinnitus that usegeneric sounds. The present therapies are only partially effective andrequire a long time. With the brain signal feedback system, we arerapidly able to suppress brain activity related to tinnitus and providerelief for this disorder.

In accordance with these and other possible variations and adaptationsof the present invention, the scope of the invention should bedetermined in accordance with the following claims, only, and not solelyin accordance with that embodiment within which the invention has beentaught.

REFERENCES

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1. An automated method for treating tinnitus by habituation tocustomized sound through use of neurological feedback, comprising thesteps of: connecting a subject through headphones to an electronic soundplayer that is connected to a PC workstation; creating a customizedsound profile for the subject's particular tinnitus by presenting aplurality of audible sound examples from tinnitus sound library softwareto the subject; allowing the subject to choose and refine the presentedsounds that most closely resemble the tinnitus sound; recording therefined sound in a digital music format to create a custom soundprofile; storing the custom sound profile recording in a computer;generating an EEG signature of the subject's brain activity in responseto the presented sound by downloading a copy of the electronic soundfile to the subject's electronic music player, presenting custom soundmost closely matching the tinnitus to stimulate the auditory system,recording the subject's response to sounds adjacent to but notspecifically corresponding to his tinnitus signature, recording thesubject's brain activity during absence of sound stimuli uploading theEEG responses to sound stimuli and to the absence of sound into thecomputer to create the EEG signature; and exposing the subject to thecustom sound for as long as practical each day wherein the EEG isactively monitored by the computer, which generates sound in responseand periodically tests the signatures for tinnitus and silence anddetermines if the tinnitus is decreasing and the silence signal isstrengthening, and wherein if these changes are not present, thecomputer slightly alters the sound stimuli and again checks forfeedback, and wherein the computer continuously monitors for thefeedback signatures and drives the sound stimuli appropriately tohabituate the subject to his tinnitus.
 2. A method for customizedhabituation treatment of tinnitus without masking sound or usingsubthreshold sound, comprising: matching narrowband sound frequency to apatient's perceived tinnitus; presenting the matched sound frequency tothe patient wherein the presented matched sound activates the samepopulation of neurons affected by tinnitus, and wherein habituationoccurs when the tinnitus and the habituating stimulus sound are as muchalike as possible; and periodically updating frequency changes asrequired for maintaining maximum habituation.
 3. An objective method fordiagnosing tinnitus by detecting changes in the dynamic responsecharacteristics of the auditory cortex induced by tinnitus, comprising:characterizing a subject's tinnitus perception by matching the pitch ofhis or her tinnitus to the frequericy of a pure sine tone generated by afunction generator a programmable logarithmic amplifier that controlledin real time by a stimulus presentation and data collection program setthe intensity of each stimulus; recording an auditory evoked potentialto a variety of tone pitches, including the tinnitus pitch wherein theincreased activation of the auditory cortex manifests itself as anincreased slope of the AR; and calculating the slope of the AR responsefor tinnitus frequency tones wherein the observed increase in the slopeof the AR in tinnitus is due to tinnitus-related activity present in theauditory cortex.
 4. A method for treating tinnitus by habituation to itssound frequency, comprising the steps of: determining the “matchingfrequency” (pitch) of a subject's tinnitus; determining the hearingthreshold for the tinnitus frequency; determining the “matchingintensity” of the subject's tinnitus; determining the hearing thresholdfor the “off” frequencies; stimulating the auditory system in two seriesof tonal stimulation first at the tinnitus frequency, and second at the“off” frequency; collecting EEG data; and giving the subjects anelectronic music player having the habituation stimulus downloadedwherein the subjects are asked to listen to it for as long as it iscomfortable each day.
 5. The method of claim 4, wherein the “matchingfrequency” is determined by 25 presenting the subjects with acontinuous, audible tone varying in pitch, and asking them to indicatethe frequency most closely matching the frequency of their tinnitus. 6.The method of claim 4, wherein to determine the threshold, subjects arepresented with a continuous tone that gradually increases in volume, andare asked to indicate when they begin to hear the tone.
 7. The method ofclaim 6, wherein the intensity at which the subjects begin to. hear thetone is considered the hearing threshold.
 8. The method of claim 4,wherein to determine the “matching intensity” subjects are presentedwith a continuous tone that increases or decreases in volume and areasked to indicate the moment when they perceive the tone as being of thesame loudness as their tinnitus.
 9. An EEG marker of tinnitus suitablefor diagnosing the presence of tinnitus, comprising: a replica of asubject's sound experience; and a measure of the subject's EEG responseto increasing intensity of the sound wherein the replica of sound isconstructed from a patients subjective determination of sound mostclosely related to the annoying sound experienced by the patient, andthe patient's EEG response is measured to determine peak amplitude ofthe N100 component.